While neurotrophic factors are best characterized for their role in nervous system development and differentiation, increasing evidence supports their involvement in the regulation of neural plasticity in adult animals. The major objective of this proposal is to continue our characterization of such a role for neurotrophic factors in the neural plasticity that accompanies chronic exposure to drugs of abuse. This competing renewal focuses on interactions between one prominent neurotrophic factor, BDNF, and the actions of 2 drugs of abuse, morphine and cocaine, at the level of the mesolimbic dopamine system, a neural pathway important for the reinforcing and addicting actions of these and other drugs of abuse. Work over the past 5 years of this grant supports three major types of interactions between BDNF and drugs of abuse. First, we (and others) have shown that exogenous BDNF, applied directly into the mesolimbic dopamine system, modifies the rewarding and locomotor-activating effects of these drugs. Exogenous BDNF also modifies the ability of drugs of abuse to produce certain characteristic biochemical and morphological adaptations in the mesolimbic dopamine system. Second, we have demonstrated that chronic exposure to morphine or cocaine causes adaptations in specific BDNF signaling proteins, and have recently obtained direct evidence that such alterations may contribute to the behavioral effects of these drugs. Third, by use of mutant mice and other approaches, which allow inducible and region-specific knockouts of BDNF or its TrkB receptor from the mesolimbic dopamine system or its afferent inputs, we have provided compelling evidence that endogenous BDNF signaling is critically involved in controlling an animal's responses to drug exposure. The goal of the proposed studies is to further characterize these interactions between BDNF and drugs of abuse, and to increasingly relate specific molecular phenomena to behavioral responses to the drugs by use of viral-mediated gene transfer and genetic mutations in mice. These proposed studies will improve our understanding of the role played by BDNF in regulating an animal's adaptations to drugs of abuse. The studies have the potential not only of shedding new light on mechanisms underlying drug addiction, but also in directing novel approaches toward the development of new treatments for addictive disorders. Moreover, in a more general sense, the proposed studies will utilize models of addiction to better understand the potent influence of BDNF on mesolimbic dopamine function in the fully differentiated, adult brain.